Resveratrol Inhibits Cancer Cell Metabolism by Down Regulating Pyruvate Kinase M2 via Inhibition of Mammalian Target of Rapamycin

Metabolism of cancer cells with pyruvate kinase M2 (PKM2) at its centre stage has assumed a prime significance in cancer research in recent times. Cancer cell metabolism, characterized by enhanced glucose uptake, production of lactate and anabolism is considered an ideal target for therapeutic interventions. Expression of PKM2 switches metabolism in favor of cancer cells, therefore, the present study was designed to investigate the hitherto unknown effect of resveratrol, a phytoalexin, on PKM2 expression and resultant implications on cancer metabolism. We observed that resveratrol down-regulated PKM2 expression by inhibiting mTOR signaling and suppressed cancer metabolism, adjudged by decreased glucose uptake, lactate production (aerobic glycolysis) and reduced anabolism (macromolecule synthesis) in various cancer cell lines. A contingent decrease in intracellular levels of ribose-5-phosphate (R5P), a critical intermediate of pentose phosphate pathway, accounted for a reduced anabolism. Consequently, the state of suppressed cancer metabolism resulted in decreased cellular proliferation. Interestingly, shRNA-mediated silencing of PKM2 inhibited glucose uptake and lactate production, providing evidence for the critical role of PKM2 and its mediation in the observed effects of resveratrol on cancer metabolism. Further, an over-expression of PKM2 abolished the observed effects of resveratrol, signifying the role of PKM2 downregulation as a critical function of resveratrol. The study reports a novel PKM2-mediated effect of resveratrol on cancer metabolism and provides a new dimension to its therapeutic potential

Gravity of human impacts mediates coral reef conservation gains

Coral reefs provide ecosystem goods and services for millions of people in the tropics, but reef conditions are declining worldwide. Effective solutions to the crisis facing coral reefs depend in part on understanding the context under which different types of conservation benefits can be maximized. Our global analysis of nearly 1,800 tropical reefs reveals how the intensity of human impacts in the surrounding seascape, measured as a function of human population size and accessibility to reefs (“gravity”), diminishes the effectiveness of marine reserves at sustaining reef fish biomass and the presence of top predators, even where compliance with reserve rules is high. Critically, fish biomass in high-compliance marine reserves located where human impacts were intensive tended to be less than a quarter that of reserves where human impacts were low. Similarly, the probability of encountering top predators on reefs with high human impacts was close to zero, even in high-compliance marine reserves. However, we find that the relative difference between openly fished sites and reserves (what we refer to as conservation gains) are highest for fish biomass (excluding predators) where human impacts are moderate and for top predators where human impacts are low. Our results illustrate critical ecological trade-offs in meeting key conservation objectives: reserves placed where there are moderate-to-high human impacts can provide substantial conservation gains for fish biomass, yet they are unlikely to support key ecosystem functions like higher-order predation, which is more prevalent in reserve locations with low human impacts

Meeting fisheries, ecosystem function, and biodiversity goals in a human-dominated world

The worldwide decline of coral reefs necessitates targeting management solutions that can sustain reefs and the livelihoods of the people who depend on them. However, little is known about the context in which different reef management tools can help to achieve multiple social and ecological goals. Because of nonlinearities in the likelihood of achieving combined fisheries, ecological function, and biodiversity goals along a gradient of human pressure, relatively small changes in the context in which management is implemented could have substantial impacts on whether these goals are likely to be met. Critically, management can provide substantial conservation benefits to most reefs for fisheries and ecological function, but not biodiversity goals, given their degraded state and the levels of human pressure they face

Developing the concept of society: Institutional domains, regimes of inequalities and complex systems in a global era

This article develops the concept of society to meet the challenge of cross-border and global processes. Global processes have made visible the inadequacy of interpreting the concept of society as if it were a nation-state, since there is a lack of congruence of institutional domains (economy, polity, civil society, violence) and regimes of inequality (class, gender, ethnicity). The article engages with two strands of intellectual heritage in sociological analysis of society as a macro concept: the differentiation of institutions and the relations of inequality. The concepts of society and societalisation are developed by hybridising these two approaches rather than selecting only one or the other. To achieve this, the concept of system is developed by drawing on complexity science. This enables the simultaneous analysis of differentiated institutional domains (economy, polity, violence, civil society) and multiple regimes of inequality without reductionism. In turn, this facilitates the fluent theorisation of variations in the temporal and spatial reach of social systems

Bmp and Nodal Independently Regulate lefty1 Expression to Maintain Unilateral Nodal Activity during Left-Right Axis Specification in Zebrafish

In vertebrates, left-right (LR) axis specification is determined by a ciliated structure in the posterior region of the embryo. Fluid flow in this ciliated structure is responsible for the induction of unilateral left-sided Nodal activity in the lateral plate mesoderm, which in turn regulates organ laterality. Bmp signalling activity has been implied in repressing Nodal expression on the right side, however its mechanism of action has been controversial. In a forward genetic screen for mutations that affect LR patterning, we identified the zebrafish linkspoot (lin) mutant, characterized by cardiac laterality and mild dorsoventral patterning defects. Mapping of the lin mutation revealed an inactivating missense mutation in the Bmp receptor 1aa (bmpr1aa) gene. Embryos with a mutation in lin/bmpr1aa and a novel mutation in its paralogue, bmpr1ab, displayed a variety of dorsoventral and LR patterning defects with increasing severity corresponding with a decrease in bmpr1a dosage. In Bmpr1a-deficient embryos we observed bilateral expression of the Nodal-related gene, spaw, coupled with reduced expression of the Nodal-antagonist lefty1 in the midline. Using genetic models to induce or repress Bmp activity in combination with Nodal inhibition or activation, we found that Bmp and Nodal regulate lefty1 expression in the midline independently of each other. Furthermore, we observed that the regulation of lefty1 by Bmp signalling is required for its observed downregulation of Nodal activity in the LPM providing a novel explanation for this phenomenon. From these results we propose a two-step model in which Bmp regulates LR patterning. Prior to the onset of nodal flow and Nodal activation, Bmp is required to induce lefty1 expression in the midline. When nodal flow has been established and Nodal activity is apparent, both Nodal and Bmp independently are required for lefty1 expression to assure unilateral Nodal activation and correct LR patterning

Pair-Wise Regulation of Convergence and Extension Cell Movements by Four Phosphatases via RhoA

Various signaling pathways regulate shaping of the main body axis during early vertebrate development. Here, we focused on the role of protein-tyrosine phosphatase signaling in convergence and extension cell movements. We identified Ptpn20 as a structural paralogue of PTP-BL and both phosphatases were required for normal gastrulation cell movements. Interestingly, knockdowns of PTP-BL and Ptpn20 evoked similar developmental defects as knockdown of RPTPα and PTPε. Co-knockdown of RPTPα and PTP-BL, but not Ptpn20, had synergistic effects and conversely, PTPε and Ptpn20, but not PTP-BL, cooperated, demonstrating the specificity of our approach. RPTPα and PTPε knockdowns were rescued by constitutively active RhoA, whereas PTP-BL and Ptpn20 knockdowns were rescued by dominant negative RhoA. Consistently, RPTPα and PTP-BL had opposite effects on RhoA activation, both in a PTP-dependent manner. Downstream of the PTPs, we identified NGEF and Arhgap29, regulating RhoA activation and inactivation, respectively, in convergence and extension cell movements. We propose a model in which two phosphatases activate RhoA and two phosphatases inhibit RhoA, resulting in proper cell polarization and normal convergence and extension cell movements

Memory development: implications for adults recalling childhood experiences in the courtroom

Adults frequently provide compelling, detailed accounts of early childhood experiences in the courtroom. Judges and jurors are asked to decide guilt or innocence based solely on these decades-old memories using 'common sense' notions about memory. However, these notions are not in agreement with findings from neuroscientific and behavioural studies of memory development. Without expert guidance, judges and jurors may have difficulty in properly adjudicating the weight of memory evidence in cases involving adult recollections of childhood experiences

Retrieval induces adaptive forgetting of competing memories via cortical pattern suppression

Remembering a past experience can, surprisingly, cause forgetting. Forgetting arises when other competing traces interfere with retrieval and inhibitory control mechanisms are engaged to suppress the distraction they cause. This form of forgetting is considered to be adaptive because it reduces future interference. The effect of this proposed inhibition process on competing memories has, however, never been observed, as behavioral methods are 'blind' to retrieval dynamics and neuroimaging methods have not isolated retrieval of individual memories. We developed a canonical template tracking method to quantify the activation state of individual target memories and competitors during retrieval. This method revealed that repeatedly retrieving target memories suppressed cortical patterns unique to competitors. Pattern suppression was related to engagement of prefrontal regions that have been implicated in resolving retrieval competition and, critically, predicted later forgetting. Thus, our findings demonstrate a cortical pattern suppression mechanism through which remembering adaptively shapes which aspects of our past remain accessible

Historical Reconstruction Reveals Recovery in Hawaiian Coral Reefs

Coral reef ecosystems are declining worldwide, yet regional differences in the trajectories, timing and extent of degradation highlight the need for in-depth regional case studies to understand the factors that contribute to either ecosystem sustainability or decline. We reconstructed social-ecological interactions in Hawaiian coral reef environments over 700 years using detailed datasets on ecological conditions, proximate anthropogenic stressor regimes and social change. Here we report previously undetected recovery periods in Hawaiian coral reefs, including a historical recovery in the MHI (∼AD 1400–1820) and an ongoing recovery in the NWHI (∼AD 1950–2009+). These recovery periods appear to be attributed to a complex set of changes in underlying social systems, which served to release reefs from direct anthropogenic stressor regimes. Recovery at the ecosystem level is associated with reductions in stressors over long time periods (decades+) and large spatial scales (>103 km2). Our results challenge conventional assumptions and reported findings that human impacts to ecosystems are cumulative and lead only to long-term trajectories of environmental decline. In contrast, recovery periods reveal that human societies have interacted sustainably with coral reef environments over long time periods, and that degraded ecosystems may still retain the adaptive capacity and resilience to recover from human impacts

OVERHEATED SECURITY? The Securitisation of Climate Change and the Governmentalisation of Security

Since the mid-2000s, climate change has become one of the defining security issues in political as well as academic debates and amongst others has repeatedly been discussed in the UN Security Council and countless high level government reports in various countries. Beyond the question whether the characterisation as ‘security issue’ is backed up by any robust empirical findings, this begs the question whether the ‘securitisation’ of climate change itself has had tangible political consequences. Moreover, within this research area there is still a lively discussion about which security conceptions apply, how to conceptualise (successful) securitisation and whether it is a (politically and normatively) desirable approach to deal with climate change. The aim of this dissertation is to shed light on these issues and particularly to contribute to a more thorough understanding of different forms or ‘discourses’ of securitisation and their political effects on a theoretical and empirical level. Theoretically, it conceptualises securitisation as resting on different forms of power, which are derived from Michel Foucault’s governmentality lectures. The main argument is that this framework allows me to better capture the ambiguous and diverse variants of securitisation and the ever-changing concept of security as well as to come to a more thorough understanding of the political consequences and powerful effects of constructing issues in terms of security. Empirically, the thesis looks at three country cases, namely the United States, Germany and Mexico. This comparative angle allows me to go beyond the existing literature on the securitisation of climate change that mostly looks at the global level, and to come to a more comprehensive and detailed understanding of different climate security discourses and their political consequences. Concerning the main results, the thesis finds that climate change has indeed been securitised very differently in the three countries and thus has facilitated diverse political consequences. These range from an incorporation of climate change into the defence sector in the US, the legitimisation of far-reaching climate policies in Germany, to the integration of climate change into several civil protection and agricultural insurance schemes in Mexico. Moreover, resting on different forms of power, the securitisation of climate change has played a key role in constructing specific actors and forms of knowledge as legitimate as well as in shaping certain identities in the face of the dangers of climate change. From a normative perspective, neither of these political consequences is purely good or bad but highly ambiguous and necessitates a careful, contextual assessment